Bax activators and uses thereof in cancer therapy

Abstract

Activators of BAX and their uses in cancer therapy are disclosed.

1 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), where the compound of Formula (I) has the structure: 
       
         
           
           
               
               
           
         
         wherein
 A is N or CH; 
 B is 
 
       
       
         
           
           
               
               
           
         
         
            where   represents the point of attachment to the scaffold; 
           X is CH or N; 
           Y is O, S, or NH; 
           R1 and R2 are independently selected from the group consisting of H, F, CI, Br, I, OH, SH, NO 2 , CF 3 , COOH, COOR6, CHO, CN, NH 2 , SO 4 H, SO 2 NH 2 , NHNH 2 , ONH 2 , NHC═(O)NHNH 2 , NHC═(O)NH 2 , NHC═(O)H, NHC(O)—OH, NHOH, OCF 3 , OCHF 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OCR6, COH, COR6, CH 2 R6, CONH 2 , CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, CH 2 N(R6, R7), N(R6,R7), or optionally substituted lower (C1-C4) alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein the optional substituent is one or more of F, CF 3 , CI, Br, I, OH, SH, NO 2 , R6, COOH, COOR6, CHO, CN, NH 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, COOR6, CH 2 N(R6, R7), and N(R6,R7); 
           R3 is selected from the group consisting of H, F, CI, Br, I, OH, SH, CF 3 , NO 2 , R6, COOH, COOR6, CHO, CN, NH 2 , SO 4 H, SO 2 NH 2 , NHNH 2 , ONH 2 , NHC═(O)NHNH 2 , NHC═(O)NH 2 , NHC═(O)H, NHC(O)—OH, NHOH, OCF 3 , OCHF 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OR6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, COOR6, CH 2 N(R6, R7), N(R6,R7), lower (C1-C4) alkyl, alkenyl, and alkynyl; 
           R10 is selected from the group consisting of H, F, CI, Br, I, OH, SH, CF 3 , NO 2 , R6, COOH, COOR6, CHO, CN, NH 2 , SO 4 H, SO 2 NH 2 , NHNH 2 , ONH 2 , NHC═(O)NHNH 2 , NHC═(O)NH 2 , NHC═(O)H, NHC(O)—OH, NHOH, OCF 3 , OCHF 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OR6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, COOR6, CH 2 N(R6, R7), N(R6,R7), lower (C1-C4) alkyl, alkenyl, and alkynyl; 
           R4 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more of F, CF 3 , CI, Br, I, OH, SH, NO 2 , R6, COOH, COOR6, CHO, CN, NH 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, COOR6, CH 2 N(R6, R7), or N(R6,R7); 
           R5 is selected from the group consisting of H, F, CI, Br, I, OH, SH, NO 2 , CF 3 , COOH, COOR6, CHO, CN, NH 2 , SO 4 H, SO 2 NH 2 , NHNH 2 , ONH 2 , NHC═(O)NHNH 2 , NHC═(O)NH 2 , NHC═(O)H, NHC(O)—OH, NHOH, OCF 3 , OCHF 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OCR6, COH, COR6, CH 2 R6, CONH 2 , CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, CH 2 N(R6, R7), N(R6,R7), or optionally substituted lower (C1-C4) alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein the optional substituent is one or more of F, CF 3 , CI, Br, I, OH, SH, NO 2 , R6, COOH, COOR6, CHO, CN, NH 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, COOR6, CH 2 N(R6, R7), or N(R6,R7); 
           R6 and R7 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkoxy, or C1-C6 thiolhaloalkoxy; 
           Provided that the compound is not any of the following two compounds: 
           (a) 1H-Pyrazole-4,5-dione, 3-phenyl-1-(4-phenyl-2-thiazolyl)-, 4-[2-(2-thiazolyl)hydrazone], or 
           (b) 1H-Pyrazole-4,5-dione, 1-[4-(4-methoxyphenyl)-2-thiazolyl]-3-phenyl-, 4-[2-(2-thiazolyl)hydrazone], 
           or a pharmaceutically acceptable salt, ester or prodrug thereof. 
         
       
     
     
         32 . The pharmaceutical composition of  claim 31 ,
 Wherein   A is N;   B is   
       
         
           
           
               
               
           
         
         R3 is selected from the group consisting of F, CI, Br, I, OH, SH, CF 3 , NO 2 , R6, COOH, COOR6, CHO, CN, NH 2 , SO 4 H, SO 2 NH 2 , NHNH 2 , ONH 2 , NHC═(O)NHNH 2 , NHC═(O)NH 2 , NHC═(O)H, NHC(O)—OH, NHOH, OCF 3 , OCHF 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OR6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, COOR6, CH 2 N(R6, R7), N(R6,R7), lower (C1-C4) alkyl, alkenyl, and alkynyl; 
         R4 is optionally substituted phenyl, wherein the optional substituent is selected from the group consisting of F, CF 3 , CI, Br, I, OH, SH, CF 3 , NO 2 , SO 4 H, SO 2 NH 2 , NHNH 2 , ONH 2 , NHC═(O)NHNH 2 , NHC═(O)NH 2 , NHC═(O)H, NHC(O)—OH, NHOH, OCF 3 , OCHF 2 , R6, COOH, COOR6, CHO, CN, NH 2 , NHR6, NHCONH 2 , NHCONHR6, NHCOR6, NHSO 2 R6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, SOR6, SO 2 R6, COOR6, CH 2 N(R6, R7), N(R6,R7), lower (C1-C4) alkyl, alkenyl, or alkynyl. 
       
     
     
         33 . The pharmaceutical composition of  claim 32 , Wherein R3 is selected from the group consisting of F, CI, Br, I, OH, SH, CF 3 , R6, COOH, COOR6, CN, NH 2 , OCF 3 , OCHF 2 , NHR6, OR6, OCR6, COR6, CH 2 R6, CON(R6,R7), OR6, COOR6, CH 2 N(R6, R7), N(R6,R7), and C1-C4 alkyl. 
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein the optional substituent for R4 is selected from the group consisting of F, CF 3 , CI, Br, I, OH, SH, CF 3 , OCF 3 , OCHF 2 , R6, COOH, COOR6, CN, NH 2 , NHR6, NHCONH 2 , NHCOR6, OCR6, COR6, CH 2 R6, CON(R6,R7), CH═N—OR6, CH═NR6, OR6, SR6, COOR6, CH 2 N(R6, R7), N(R6,R7), and C1-C4 alkyl. 
     
     
         35 . The pharmaceutical composition of  claim 32 , wherein R4 is phenyl. 
     
     
         36 . The pharmaceutical composition of  claim 32 , wherein X is N, Y is S. 
     
     
         37 . The pharmaceutical composition of  claim 32 , wherein R5 is H. 
     
     
         38 . The pharmaceutical composition of  claim 32 , wherein R1 and R2 are independently selected from the group consisting of H, F, CI, Br, I, OH, CF 3 , COOH, COOR6, CN, NH 2 , OCF 3 , OCHF 2 , NHR6, OCR6, CH 2 R6, CH 2 N(R6, R7), N(R6,R7), and C1-C4 alkyl. 
     
     
         39 . The pharmaceutical composition of  claim 32 , wherein R1 and R2 are independently selected from the group consisting of H, F, CI, Br, I, OH, CF 3 , COOH, CN, NH 2 , OCF 3 , and C1-C4 alkyl. 
     
     
         40 . The pharmaceutical composition of  claim 32 , wherein R10 is H. 
     
     
         41 . The pharmaceutical composition of  claim 32 , wherein R10 is selected from the group consisting of F, CI, Br, I, OH, CF 3 , R6, COOH, COOR6, CN, NH 2 , SOCF 3 , OCHF 2 , NHR6, NHCOR6, OR6, OCR6, COR6, CH 2 R6, COOR6, N(R6,R7), and C1-C4 alkyl. 
     
     
         42 . The pharmaceutical composition of  claim 31 ,
 Wherein   A is N;   B is   
       
         
           
           
               
               
           
         
         Wherein R4 is optionally substituted heteroaryl. 
       
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein X is N, Y is S, and R4 is optionally substituted thiophene or furan. 
     
     
         44 . The pharmaceutical composition of  claim 31 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         45 . The pharmaceutical composition of  claim 31 , wherein the compound is present in an amount effective to activate BCL-2-associated X-protein (BAX). 
     
     
         46 . A method of treating a cancer in a subject comprising administering to the subject a pharmaceutical composition of claim  1 , wherein the compound is in an amount effective to activate BCL-2-associated X-protein (BAX) in a subject. 
     
     
         47 . The method of  claim 46 , wherein the cancer is breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain or spinal cord cancer, primary brain carcinoma, medulloblastoma, neuroblastoma, glioma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, stomach cancer, kidney cancer, placental cancer, cancer of the gastrointestinal tract, non-small cell lung cancer (NSCLC), head or neck carcinoma, breast carcinoma, endocrine cancer, eye cancer, genitourinary cancer, cancer of the vulva, ovary, uterus or cervix, hematopoietic cancer, myeloma, leukemia, lymphoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue cancer, soft-tissue sarcoma, osteogenic sarcoma, sarcoma, primary macroglobulinemia, central nervous system cancer and retinoblastoma. 
     
     
         48 . The method of  claim 46 , wherein the cancer is a leukemia or a solid tumor. 
     
     
         49 . The method of  claim 46 , wherein the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML). 
     
     
         50 . A method of inducing apoptosis in cancer cells and/or in leukemia stem cells in a subject comprising administering to the subject the compound in the pharmaceutical composition of claim  1  in an amount effective to induce apoptosis in cancer cells and/or in leukemia stem cells in a subject. 
     
     
         51 . The method of  claim 50 , wherein the cancer cells are leukemia cells or solid tumor cells.